Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by the expansion of CGG-trinucleotide repeats in the 5? untranslated region (UTR) of the gene fragile-X mental retardation 1 (FMR1). An atypical mode of protein translational initiation, known as repeat-associated, non- ATG (RAN) translation, plays a key role in the pathogenesis of FXTAS and other nucleotide-expansion disorders by triggering synthesis of aberrant homopolymeric proteins that accumulate in neuronal inclusions and elicit toxicity in disease models. To understand how RAN translation works and how it might be suppressed, I performed a candidate-based screen for modulators of RAN translation in a Drosophila melanogaster model of FXTAS. This screen identified the RNA helicase belle (DDX3, in humans) as critical for RAN translation in both flies and human cell-based assays. This proposal will determine how DDX3 facilitates RAN translation and whether genetic inhibition of belle/DDX3 alleviates RAN translation-dependent toxicity in Drosophila and mammalian neurons. This work should provide mechanistic insights into how RAN translation occurs while providing a roadmap for rational therapeutic development in FXTAS and other repeat expansion disorders.